1. Field of the Invention
This invention relates to derivatives of piperidine-2,6-dione, also known as glutarimide, its preparation and pharmaceutical compositions containing it.
2. Description of the Prior Art
U.S. Pat. No. 2,673,205 (Ciba) claims 3,3-disubstitutedglutarimides of formula ##STR2## where R.sup.1 represents an aliphatic hydrocarbyl group of 1 to 6 carbon atoms and V represents a phenyl or pyridyl group, and R.sup.2 represents hydrogen or a substituent group such as alkyl, acyl, phenyl or benzyl. The class of compounds claimed in U.S. Pat. No. 2,673,205 is stated to have an anti-convulsive effect. However, the preferred compound, 3-ethyl-3-phenylglutarimide was subsequently marketed as the sedative and hypnotic agent glutethimide. The later U.S. Pat. No. 2,848,455 (Ciba) claims 3-methyl and -ethyl-3-(4-aminophenyl)glutarimides as anti-convulsive agents. The 3-ethyl compound is known as aminoglutethimide.
Certain compounds of formula (1) wherein R.sup.1 is a straight chain alkyl group of 1 to 4 carbon atoms and V is a phenyl, 1,2-cyclohexenyl or cylcohexyl group are reported to have varying degrees of CNS activity, see J. Knabe et al., Arch. Pharm. 317 614-619 (1984).
The present invention is concerned with an entirely different field of therapy, namely anti-cancer therapy, specifically the treatment of oestrogen-dependent tumours. Such tumours are most commonly produced in the breast tissue of female mammals. Within the last 5 years or so aminoglutethimide has come seriously into the reckoning for treatment of advanced breast cancer in post-menopausal patients. Its advantages over tamoxifen have been set out in a recent paper by I. E. Smith et al., British Medical Journal, 283, 1432-1434 (1981). One important factor in the success of aminoglutethimide in this connection is its ability to inhibit in vivo the activity of the enzyme aromatase in peripheral tissue. This enzyme is required for the conversion of androgens into oestrogens, viz. androstenedione to oestrone and testosterone to oestradiol. Aminogluthethimide therefore breaks the metabolic pathway to oestrogens. Unfortunately, however, aminoglutethimide also inhibits the enzyme desmolase which is required for the metabolic conversion of cholesterol to corticosteroids. Since the body needs corticosteroids, treatment with aminoglutethimide has to be supplemented by cortisone replacement therapy. Furthermore, depletion of corticosteroids causes a reflex rise in adrenocorticotrophic hormone (ACTH) which stimulates the conversion of cholesterol to pregnenolone by the enzyme desmolase and consequently the production of oestrogen precursors.
Recently, it has been found that the compound 3-ethyl-3-(4-pyridyl)glutarimide inhibits aromatase but not desmolase. This finding was surprising in that neither its nearest phenyl analogue, aminoglutethimide, nor its nearest pyridyl analogues, having the pyridine ring N-atom in the 2- or 3-position, showed this property. The finding is the subject of PCT Patent Application GB No. 84/00425 (National Research Development Corporation) designating U.S. and Japan, published 20th June 1985 as WO No. 85/02618 and UK and foreign equivalents thereof, all claiming priority of 9th December 1983. See also A. B. Foster et al., J. Med Chem. 28, 200-204 (1985).